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A Systems Biology Roadmap to Decode mTOR Control System in Cancer

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Abstract

Mechanistic target of rapamycin (mTOR) is a critical protein in the regulation of cell fate decision making, especially in cancer cells. mTOR acts as a signal integrator and is one of the main elements of interactions among the pivotal cellular processes such as cell death, autophagy, metabolic reprogramming, cell growth, and cell cycle. The temporal control of these processes is essential for the cellular homeostasis and dysregulation of mTOR signaling pathway results in different phenotypes, including aging, oncogenesis, cell survival, cell growth, senescence, quiescence, and cell death. In this paper, we have proposed a systems biology roadmap to study mTOR control system, which introduces the theoretical and experimental modalities to decode temporal and dynamical characteristics of mTOR signaling in cancer.

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References

  1. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6(9):729

    Article  CAS  PubMed  Google Scholar 

  2. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(20):3589–3594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Inoki K, Corradetti MN, Guan K-L (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37(1):19

    Article  CAS  PubMed  Google Scholar 

  5. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Sci Signal 2(67):pe24-pe24

    Article  Google Scholar 

  6. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tyson JJ, Baumann WT, Chen C, Verdugo A, Tavassoly I, Wang Y, Weiner LM, Clarke R (2011) Dynamic modelling of oestrogen signalling and cell fate in breast cancer cells. Nat Rev Cancer 11(7):523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dann SG, Selvaraj A, Thomas G (2007) mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13(6):252–259

    Article  CAS  PubMed  Google Scholar 

  9. Vergès B, Cariou B (2015) mTOR inhibitors and diabetes. Diabetes Res Clin Pract 110(2):101–108

    Article  PubMed  CAS  Google Scholar 

  10. Jia G, Aroor AR, Martinez-Lemus LA, Sowers JR (2014) Overnutrition, mTOR signaling, and cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol 307(10):R1198–R1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Perl A (2016) Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol 12(3):169

    Article  CAS  PubMed  Google Scholar 

  12. Ginzberg MB, Chang N, D’Souza H, Patel N, Kafri R, Kirschner MW (2018) Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity. Elife 7:e26957

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xu S, Cai Y, Wei Y (2014) mTOR signaling from cellular senescence to organismal aging. Aging Dis 5(4):263

    PubMed  Google Scholar 

  14. Lamming DW, Ye L, Sabatini DM, Baur JA (2013) Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Investig 123(3):980–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ginzberg MB, Kafri R, Kirschner M (2015) On being the right (cell) size. Science 348(6236):1245075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Garratt M, Nakagawa S, Simons MJ (2016) Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction. Aging Cell 15(4):737–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Powell JD, Pollizzi KN, Heikamp EB, Horton MR (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39–68

    Article  CAS  PubMed  Google Scholar 

  18. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460(7251):108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mannick JB, Morris M, Hockey HUP, Roma G, Beibel M, Kulmatycki K, Watkins M, Shavlakadze T, Zhou W, Quinn D et al (2018) TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med 10(449):ee1564

    Article  CAS  Google Scholar 

  20. Huang S, Houghton PJ (2003) Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3(4):371–377

    Article  CAS  PubMed  Google Scholar 

  21. Faivre S, Kroemer G, Raymond E (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671

    Article  CAS  PubMed  Google Scholar 

  22. Benjamin D, Colombi M, Moroni C, Hall MN (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10(11):868

    Article  CAS  PubMed  Google Scholar 

  23. Neuhaus P, Klupp J, Langrehr JM (2001) mTOR inhibitors: an overview. Liver Transpl 7(6):473–484

    Article  CAS  PubMed  Google Scholar 

  24. Vezina C, Kudelski A, Sehgal S (1975) Rapamycin (AY-22, 989), a new antifungal antibiotic. J Antibiot 28(10):721–726

    Article  CAS  Google Scholar 

  25. Janku F, Yap TA, Meric-Bernstam F (2018) Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol 15(5):273

    Article  CAS  PubMed  Google Scholar 

  26. Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sahra IB, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti J-F, Giorgetti-Peraldi S, Bost F (2011) Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Can Res 71(13):4366–4372

    Article  CAS  Google Scholar 

  28. Tavassoly I, Goldfarb J, Iyengar R (2018) Systems biology primer: the basic methods and approaches. Essays Biochem 62(4):487–500

    Article  PubMed  Google Scholar 

  29. Din FVN, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142(7):1504–1515.e1503

    Article  CAS  PubMed  Google Scholar 

  30. Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15(3):155

    Article  CAS  PubMed  Google Scholar 

  31. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hansen J, Meretzky D, Woldesenbet S, Stolovitzky G, Iyengar R (2017) A flexible ontology for inference of emergent whole cell function from relationships between subcellular processes. Sci Rep 7(1):17689

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Clarke R, Shajahan AN, Wang Y, Tyson JJ, Riggins RB, Weiner LM, Bauman WT, Xuan J, Zhang B, Facey C (2011) Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer. Horm Mol Biol Clin Investig 5(1):35–44

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Clarke R, Cook KL, Hu R, Facey CO, Tavassoly I, Schwartz JL, Baumann WT, Tyson JJ, Xuan J, Wang Y (2012) Endoplasmic reticulum stress, the unfolded protein response, autophagy, and the integrated regulation of breast cancer cell fate. Can Res 72(6):1321–1331

    Article  CAS  Google Scholar 

  35. Barabási A-L, Gulbahce N, Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12(1):56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Dorvash M, Farahmandnia M, Mosaddeghi P, Farahmandnejad M, Saber H, Khorraminejad-Shirazi M, Azadi A, Tavassoly I (2019) Dynamic modeling of signal transduction by mTOR complexes in cancer. J Theor Biol 483:109992

    Article  CAS  PubMed  Google Scholar 

  37. Meng D, Frank AR, Jewell JL (2018) mTOR signaling in stem and progenitor cells. Development 145(1):dev152595

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Tavassoly I, Parmar J, Shajahan-Haq A, Clarke R, Baumann W, Tyson J (2015) Dynamic modeling of the interaction between autophagy and apoptosis in mammalian cells. CPT Pharmacomet Syst Pharmacol 4(4):263–272

    Article  CAS  Google Scholar 

  39. Tavassoly I (2015) Dynamics of cell fate decision mediated by the interplay of autophagy and apoptosis in cancer cells mathematical modeling and experimental observations. Springer, New York

    Google Scholar 

  40. Parmar JH, Cook KL, Shajahan-Haq AN, Clarke PA, Tavassoly I, Clarke R, Tyson JJ, Baumann WT (2013) Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer. Interface Focus 3(4):20130012

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shaw RJ, Cantley LC (2006) Ras, PI (3) K and mTOR signalling controls tumour cell growth. Nature 441(7092):424

    Article  CAS  PubMed  Google Scholar 

  42. Chatterjee A (2015) Control of cell cycle progression by mTOR

  43. Kim J, Guan K-L (2019) mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol 21(1):63

    Article  CAS  PubMed  Google Scholar 

  44. Efeyan A, Sabatini DM (2010) mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 22(2):169–176

    Article  CAS  PubMed  Google Scholar 

  45. Rosner M, Fuchs C, Siegel N, Valli A, Hengstschläger M (2009) Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle. Hum Mol Genet 18(17):3298–3310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nishitani S, Horie M, Ishizaki S, Yano H (2013) Branched chain amino acid suppresses hepatocellular cancer stem cells through the activation of mammalian target of rapamycin. PLoS One 8(11):e82346

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R (2012) TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion. J Cell Sci 125(5):1259–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Loos B, Engelbrecht A-M (2009) Cell death: a dynamic response concept. Autophagy 5(5):590–603

    Article  CAS  PubMed  Google Scholar 

  49. Laplante M, Sabatini DM (2012) mTOR signaling. Cold Spring Harb Perspect Biol 4(2):a011593

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM (2012) A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485(7396):109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Domhan S, Schwager C, Wei Q, Muschal S, Sommerer C, Morath C, Wick W, Maercker C, Debus J, Zeier M (2014) Deciphering the systems biology of mTOR inhibition by integrative transcriptome analysis. Curr Pharm Des 20(1):88–100

    Article  CAS  PubMed  Google Scholar 

  52. Fu Y, Zheng X, Jia X, Binderiya U, Wang Y, Bao W, Bao L, Zhao K, Fu Y, Hao H (2016) A quantitative transcriptomic analysis of the physiological significance of mTOR signaling in goat fetal fibroblasts. BMC Genomics 17(1):879

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485(7396):55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hsieh H-J, Zhang W, Lin S-H, Yang W-H, Wang J-Z, Shen J, Zhang Y, Lu Y, Wang H, Yu J (2018) Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery. Nat Commun 9(1):3982

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, Lemieux S, Perreault C, Roux PP, Kitano H (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6(1):453

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chen EY, Xu H, Gordonov S, Lim MP, Perkins MH, Ma’ayan A (2011) Expression2Kinases: mRNA profiling linked to multiple upstream regulatory layers. Bioinformatics 28(1):105–111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Sorribes I, Basu A, Brady R, Enriquez-Navas P, Feng X, Kather J, Nerlakanti N, Stephens R, Strobl M, Tavassoly I (2019) Harnessing patient-specific response dynamics to optimize evolutionary therapies for metastatic clear cell renal cell carcinoma-learning to adapt. bioRxiv, 563130. https://doi.org/10.1101/563130

  58. Rockne RC, Hawkins-Daarud A, Swanson KR, Sluka JP, Glazier JA, Macklin P, Hormuth DA, Jarrett AM, Lima EABF, Tinsley Oden J et al (2019) The 2019 mathematical oncology roadmap. Phys Biol 16(4):041005

    Article  PubMed  PubMed Central  Google Scholar 

  59. Bibi Z, Ahmad J, Siddiqa A, Paracha RZ, Saeed T, Ali A, Janjua HA, Ullah S, Ben Abdallah E, Roux O (2017) Formal modeling of mTOR associated biological regulatory network reveals novel therapeutic strategy for the treatment of cancer. Front Physiol 8:416

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sulaimanov N, Klose M, Busch H, Boerries M (2017) Understanding the mTOR signaling pathway via mathematical modeling. Wiley Interdiscip Rev Syst Biol Med 9(4):e1379

    PubMed Central  Google Scholar 

  61. Tyson JJ, Chen K, Novak B (2001) Network dynamics and cell physiology. Nat Rev Mol Cell Biol 2(12):908

    Article  CAS  PubMed  Google Scholar 

  62. Wang R-S, Saadatpour A, Albert R (2012) Boolean modeling in systems biology: an overview of methodology and applications. Phys Biol 9(5):055001

    Article  PubMed  CAS  Google Scholar 

  63. Albert I, Thakar J, Li S, Zhang R, Albert R (2008) Boolean network simulations for life scientists. Source Code Biol Med 3(1):16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zadeh LA (1965) Fuzzy sets. Inf Control 8(3):338–353

    Article  Google Scholar 

  65. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP (2012) A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci Signal 5(217):ra25–ra25

    Article  Google Scholar 

  66. Sonntag AG, Dalle Pezze P, Shanley DP, Thedieck K (2012) A modelling–experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. FEBS J 279(18):3314–3328

    Article  CAS  PubMed  Google Scholar 

  67. Kriete A, Bosl WJ, Booker G (2010) Rule-based cell systems model of aging using feedback loop motifs mediated by stress responses. PLoS Comput Biol 6(6):e1000820

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Wu M, Yang X, Chan C (2009) A dynamic analysis of IRS-PKR signaling in liver cells: a discrete modeling approach. PLoS One 4(12):e8040

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Dalle Pezze P, Ruf S, Sonntag AG, Langelaar-Makkinje M, Hall P, Heberle AM, Navas PR, Van Eunen K, Tölle RC, Schwarz JJ (2016) A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Nat Commun 7:13254

    Article  PubMed  CAS  Google Scholar 

  70. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K (2016) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 12(1):1–222

    Article  PubMed  PubMed Central  Google Scholar 

  71. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8(9):741

    Article  CAS  PubMed  Google Scholar 

  72. Jung CH, Seo M, Otto NM, Kim D-H (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7(10):1212–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Blagosklonny MV (2008) Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res 11(4):801–808

    Article  CAS  PubMed  Google Scholar 

  74. Novák B, Tyson JJ (2008) Design principles of biochemical oscillators. Nat Rev Mol Cell Biol 9(12):981

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Milo R, Shen-Orr S, Itzkovitz S, Kashtan N, Chklovskii D, Alon U (2002) Network motifs: simple building blocks of complex networks. Science 298(5594):824–827

    Article  CAS  PubMed  Google Scholar 

  76. Tyson JJ, Novák B (2010) Functional motifs in biochemical reaction networks. Annu Rev Phys Chem 61:219–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tian X-J, Zhang X-P, Liu F, Wang W (2009) Interlinking positive and negative feedback loops creates a tunable motif in gene regulatory networks. Phys Rev E 80(1):011926

    Article  CAS  Google Scholar 

  78. Tsai TY-C, Choi YS, Ma W, Pomerening JR, Tang C, Ferrell JE (2008) Robust, tunable biological oscillations from interlinked positive and negative feedback loops. Science 321(5885):126–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nazio F, Cecconi F (2017) Autophagy up and down by outsmarting the incredible ULK. Autophagy 13(5):967–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lamming DW, Bar-Peled L (2019) Lysosome: the metabolic signaling hub. Traffic 20(1):27–38

    Article  CAS  PubMed  Google Scholar 

  81. Ryzhikov M, Ehlers A, Steinberg D, Xie W, Oberlander E, Brown S, Gilmore PE, Townsend RR, Lane WS, Dolinay T (2019) Diurnal rhythms spatially and temporally organize autophagy. Cell Rep 26(7):1880–1892.e1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Szymańska P, Martin KR, MacKeigan JP, Hlavacek WS, Lipniacki T (2015) Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. PLoS One 10(3):e0116550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sachdeva UM, Thompson CB (2008) Diurnal rhythms of autophagy: implications for cell biology and human disease. Autophagy 4(5):581–589

    Article  CAS  PubMed  Google Scholar 

  84. Ma D, Panda S, Lin JD (2011) Temporal orchestration of circadian autophagy rhythm by C/EBPβ. EMBO J 30(22):4642–4651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nazio F, Carinci M, Valacca C, Bielli P, Strappazzon F, Antonioli M, Ciccosanti F, Rodolfo C, Campello S, Fimia GM (2016) Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. J Cell Biol 215(6):841–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cao R, Obrietan K (2010) mTOR signaling and entrainment of the mammalian circadian clock. Mol Cell Pharmacol 2(4):125

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ramanathan C, Kathale ND, Liu D, Lee C, Freeman DA, Hogenesch JB, Cao R, Liu AC (2018) mTOR signaling regulates central and peripheral circadian clock function. PLoS Genet 14(5):e1007369

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Toledo M, Batista-Gonzalez A, Merheb E, Aoun ML, Tarabra E, Feng D, Sarparanta J, Merlo P, Botrè F, Schwartz GJ (2018) Autophagy regulates the liver clock and glucose metabolism by degrading CRY1. Cell Metab 28(2):268–281.e264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ma D, Li S, Molusky MM, Lin JD (2012) Circadian autophagy rhythm: a link between clock and metabolism? Trends Endocrinol Metab 23(7):319–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Devalla HD, Schwach V, Ford JW, Milnes JT, El-Haou S, Jackson C, Gkatzis K, Elliott DA, de Sousa Lopes SMC, Mummery CL (2015) Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology. EMBO Mol Med 7(4):394–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, Imarisio S, Jahreiss L, Sarkar S, Futter M, Menzies FM (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13(4):453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458(7242):1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maiese K (2017) Moving to the rhythm with clock (circadian) genes, autophagy, mTOR, and SIRT1 in degenerative disease and cancer. Curr Neurovasc Res 14(3):299–304

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Savvidis C, Koutsilieris M (2012) Circadian rhythm disruption in cancer biology. Mol Med 18(9):1249–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang S, Tsun Z-Y, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W (2015) Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347(6218):188–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. López-Otín C, Galluzzi L, Freije JM, Madeo F, Kroemer G (2016) Metabolic control of longevity. Cell 166(4):802–821

    Article  PubMed  CAS  Google Scholar 

  97. Rubinsztein DC, Mariño G, Kroemer G (2011) Autophagy and aging. Cell 146(5):682–695

    Article  CAS  PubMed  Google Scholar 

  98. Leontieva OV, Demidenko ZN, Gudkov AV, Blagosklonny MV (2011) Elimination of proliferating cells unmasks the shift from senescence to quiescence caused by rapamycin. PLoS One 6(10):e26126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mathiassen SG, De Zio D, Cecconi F (2017) Autophagy and the cell cycle: a complex landscape. Front Oncol 7:51

    Article  PubMed  PubMed Central  Google Scholar 

  100. Kriel J, Loos B (2019) The good, the bad and the autophagosome: exploring unanswered questions of autophagy-dependent cell death. Cell Death Differ 26(4):640–652

    Article  PubMed  PubMed Central  Google Scholar 

  101. Tavassoly I, Hu Y, Zhao S, Mariottini C, Boran A, Chen Y, Li L, Tolentino RE, Jayaraman G, Goldfarb J et al (2019) Genomic signatures defining responsiveness to allopurinol and combination therapy for lung cancer identified by systems therapeutics analyses. Mol Oncol 13(8):1725–1743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zaytseva YY, Valentino JD, Gulhati P, Evers BM (2012) mTOR inhibitors in cancer therapy. Cancer Lett 319(1):1–7

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammadreza Dorvash

  2. Cell and Molecular Medicine Student Research Group, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammadreza Dorvash & Mohammad Farahmandnia

  3. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY, 10029, USA

    Iman Tavassoly

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  1. Mohammadreza Dorvash
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Dorvash, M., Farahmandnia, M. & Tavassoly, I. A Systems Biology Roadmap to Decode mTOR Control System in Cancer. Interdiscip Sci Comput Life Sci 12, 1–11 (2020). https://doi.org/10.1007/s12539-019-00347-6

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